Poxviruses express soluble and membrane-bound proteins that directly modulate the host immune response. Recently, a new strategy of immune modulation was revealed by the discovery (by the applicant and his mentor) of a soluble IL-18 binding protein (IL18BP) in both poxviruses and in their mammalian hosts. IL18 is a proinflammatory cytokine that enhances immune responses and protects against microbial infection and tumors in murine models. The viral and host IL18BPs can bind to IL-18 with high affinities and inhibit IL-18-mediated IFNg induction. A detailed understanding of interactions involving IL-18, its receptor and IL18BP is needed, and has therapeutic implications. The availability of IL18BPs from six different genera of poxviruses has allowed detailed molecular studies to be performed on the mechanism of IL-18 recognition and inhibition. The applicant proposes the following specific aims: First, to further characterize the structure/function relationship of the IL-18 and IL18BP interaction by examining binding in different poxvirus species. Then to determine the molecular mechanism of IL18BP function by identifying in human IL-18 the main binding site for IL18BPs and determining whether the site is shared by IL18R. Finally, to investigate the functions of two molluscum contagiosum virus (MCV) proteins that share significant homology with IL18BP but that have no IL-18 binding activity, and determine whether IL18BPs bind and inhibit other cytokines that are closely related to IL-18.